1. Field of the Invention
The present invention relates to a method and apparatus for measuring blood nuclear magnetic resonance (NMR) longitudinal axis relaxation time, and more particularly, to a method and apparatus capable of more accurately measuring NMR longitudinal axis relaxation time by minimizing the influence of the amount of blood.
2. Description of the Related Art
In the medical field, NMR imaging systems and NMR spectrometers for diagnosis have been used for a long time. These imaging systems and spectrometers can specifically describe the structure of a living organism and/or the structure of an organ in real time (Hinshaw et al. Display of Cross-Sectional Anatomy by Nuclear Magnetic Resonance Imaging. Brit. J. Radiol., 51: 273 (1978)., Edelstein et al. Spin Warp NMR Imaging and Applications to Human Whole-Body Imaging. Phys. Med. Biol., 25(4): 751-6 (1980)., Crooks et al. Nuclear Magnetic Resonance Whole-Body Imager Operating at 3.5 kGauss. Radiology, 143(1): 169-174 (1982).). These descriptions can be used to study a change in or a present condition of a body. Even though there is a structural change or an anatomic change, a change in image contrast can be tracked using a special chemical control reagent. Such a contrast change may occur as a natural result. A change in a function often occurs prior to a structural change or morphological change. This leads to a change in a chemical reaction rate and metabolic activity of a tissue with disease and, in turn, affects water proton relaxation time and NMR image contrast. This scheme is particularly useful for diagnosing diseases and other medical conditions, such as cancer or inflammation. Multiple sources verify that such information is very useful in the medical field (T. Araki, T. Inouye, T. Motazaki and M. Iio, Proceedings of the 2nd Annual Meeting of the Society of Magnetic Resonance in Medicine, Berkeley, Calif., 1983, pp. 3-4; C. J. G. Bakker and J. Vriend, Phys. Med. Biol., 28, 331, 1983; L. E. Barroilhet and P. R. Moran, Med. Phys. 2, 191, 1975; P. T. Beall, Magn. Reson. Imag. 1, 189, 1982; P. T. Beall, et al. J. Natl. Cancer Inst., 64, 335 1980; P. S. Belton, R. R. Jackson and K. J. Packer, Biochim. Biophys. Acta., 286, 16, 1972; D. R. Bailes et al., Clin. Radiolog., 33, 395, 1982). A typical NMR imaging apparatus provides information about the amount of water present in different tissues of a body or organs. Qualitatively, the apparatus provides a relaxation rate through image contrast. The use of additional hardware and software provides more accurate data of the relaxation rate. However, this additional capability has an associated increase in cost. An NMR imaging apparatus is expensive and needs skilled engineers and special infrastructure for installation and operation. Due to all these factors, the apparatus has been used only in large hospitals or medical centers.
It is well known that the relaxation time is useful as a critical diagnostic factor in medical diagnosis. Relaxation time in organism tissue was originally studied a long time ago. Many of the studies have been performed on numerous types of animal tissues and on human body tissues.
The relaxation time was initially studied by Odelblad, et al. in the late 1950's (E. Odelblad and G. Lindstrom, Acta Radiol. 43, 469, 1955; E. Odelblad and U. Bryhn, Acta Radiiol., 47, 315 1957; E. Odelblad and B. Westin, Acta Radiol., 49, 389, 1958). Damadian disclosed a study on elevated relaxation time of cancer patients (R. Damadian, Science, 171, 1151 1971). In 1975, Eggleston et al. disclosed a change in relaxation time in a number of diseased tissues (J. C. Eggleston, L. A. Saryan and D. P. Hollis, Cancer Res., 35, 1326 1975). This marked a beginning of studies in the field of NMR imaging systems, which has developed into NMR imaging and spectrum techniques actually used for medical treatment.
It was initially difficult to discover the regularity of relaxation time in the same species. This is because there are differences between schemes and calculating ways used by several researchers and between sample measuring and processing conditions. External physical factors, such as resonance frequency, temperature, and fabrication and storing conditions for in vitro samples, significantly affect the data. It was found that dependency of the relaxation time on the frequency is correlated with rotational time of a protein molecule. This rotational time of the protein molecule determines relaxation time of an adjacent water molecule. The relaxation time of water in a tissue was observed to depend on a temperature change because the dynamic structure of water in an organism is sensitive to temperature. Clearly, relaxation times should be compared to each other at the same frequency and temperature for each sample in order to use relaxation time as an identification factor. In addition, a sample fabricating and storing method should be finely controlled and standardized to obtain a value of a tissue number that is reproducible and can be compared with respect to the relaxation time.
It was found that observed relaxation time depends on a measuring method used in an experiment. This is because relaxation generally has a multi-exponential characteristic in a heterogeneous organism tissue. When an inversion recovery pulse sequence is used for relaxation time measurement, approximation such as a null method, a 1/e method, initial rate approximation, and a single exponential fitting method may be used to calculate the relaxation time. All of these schemes result in a somewhat different relaxation time. Therefore, a consistent relaxation time calculation method, as well as temperature and frequency, is needed for the comparison of the relaxation time in the experiment.
Most studies on relaxation time behavior in an organism tissue were conducted within a test tube. As the study in this field is standardized to some extent and as data and statistics are accumulated, knowledge and standardized methods develop (P. A. Bottomley. T. H. Foster, R. E. Argersinger, L. M. Pfeifer, Med. Phys. 11 (4), July/August 1984, G. B. Friedmann, Magnetic Resonance Review 6, 4, 247-307 (1981)). It was found that the relaxation time of a number of species and types of tissues is a function of an NMR frequency, temperature, in vivo to in vitro, and time and age of extraction. It was found that the relaxation time is mainly affected by the NMR frequency and the tissue type.
The tissue frequency change may be represented by the following Equation:T1=Av−B,  Equation 1where A and B are tissue dependent constants at frequencies of 1-100 MHz, T1 is longitudinal axis relaxation time, and v is an angular frequency. T2 is a multiple-element. Transverse axis proton NMR relaxation time, T2, was found to be essentially independent of the NMR frequency and to mainly depend on the type of tissue.
In the 1980's, much attention was concentrated on studies about relaxation time behavior in pathology and disease fields. Accumulated experience and results in these fields provide some information to actual medical treatment.
In most pathology, for example different types of cancers, it was observed that the tissue relaxation time is significantly increased. In a study by bottomley et al., authors checked, analyzed and summarized longitudinal axis T1 and transverse axis T2 proton NMR relaxation time of pathological human and animal tissue at 1-100 MHz, which is a function of tissue genesis, NMR frequency, temperature, species, and an in vivo to in vitro state. T1 data of bone, brain, breast, kidney, liver, muscle, pancreas and spleen at a specific disease state may be simply represented by T1=Av−B at 1-100 MHz, where A and B are pathology dependent constants which are experimentally determined and v is frequency. The pathological T2 tissue value is essentially independent of the NMR frequency. When the tissue value is independent as a result of statistical analysis of the relaxation data, it was revealed that the T1 value of most tumor and edema tissue and the T2 value of breast, liver and muscle tumor have increased compared to a normal value, but is not significantly different from other tumor and pathology.
A series of small tissue piece samples were stereo-tactically extracted from patients with glial brain tumors. Some tissue factors (water content, specific gravity of dried tissue, electrical impedance, histopathological and cytological tissue examination) of each sample were measured, and associated with NMR relaxation time of each sample. Thirty-two samples of human brain tumor were used for this measurement. The result is as follows. The longitudinal axis and transverse axis relaxation time, water content and dried tissue specific gravity of the brain tumor samples were significantly increased but the electrical impedance was reduced. There was no noticeable correlation between the relaxation time and the pathological diagnosis. However, it was found from a single analysis case that the piece sample of the tumor had a linear relationship between the longitudinal axis relaxation time and the water content. As the slope of the relationship increases, the malignant of the tumor increases. The structural change of a tumor cell giant molecule (nucleic acid and protein) can be predicted from the increases of both the water content and a dried tissue ratio in the tumor tissue (P. A. bottomley, C. J. Hardy, R. E. Argersinger, G. Allen-Moore, Medical Physics 14, no. 1, 1-37, January ?February 1987.).
This finding is very important. If there is a change in the structure and function of a biologic giant molecule as the disease proceeds, it means that there is great possibility that the change may be reflected to a change in the relaxation time. It can be predicted that cancer or malignant disease as well as edema have such an effect. There are a number of documents verifying such predictions. For example, Papish et al. tracked longitudinal axis and transverse axis relaxation time levels of serum of 197 healthy persons, 180 patients having no malignant tumor history, and 345 cancer patients having tumor at different portions. These factors are not related with sex or age of the patients. The relaxation time value of the cancer patients was greater than the patients having no tumor and much greater than the healthy persons' relaxation time value. On average, the patients having no tumor exhibited an increased longitudinal axis relaxation time of 0.17s compared to the healthy persons, and the patients having tumor exhibited an increase by 0.27 s (E. A. Papish, T. Y. Tyomkina, N. F. Karyakina, Meditsinskaya Radiologiya vol.33, no.8: 47-50, August 1988.).
A second group of 180 patients had different diseases such as tuberculosis, gastric ulcer, gastritis and fibrous tumor. Only malignant diseases do not increase the relaxation time. The relaxation time change can be tracked through a study on an organ tissue with disease or a study on liquid that is common to all organisms. Such liquids are blood and lymph. Referring to the references, it can be seen that a change in the relaxation time of blood and blood plasma has been studied, and that relaxation time is typically increased in a number of histopathological cases (Supra, G. B. Friedmann, Magnetic Resonance Review 6, 4, 247-307 (1981), E. A. Papish, T. Y. Tyomkina, N. F. Karyakina, Meditsinskaya Radiologiya vol.33, no.8: 47-50, August 1988, O. P. Revokatov, M. G. Gangardt, V. V. Murashko, A. K. Zhuravlev, Biofizika v.27, no 2, 336-338, 1982, A. Koivula, K. Suominen, T. Timonen, K. Kiviniitty, Physics in Medicine and Biology v. 27, no. 7, 937-947, July 1982.).). In a study by Revokatov et al. spin-lattice and spin-spin relaxation time, and a self-diffusion coefficient of water molecule in serum and blood plasma of healthy persons, patients with disease other than cancer, and cancer patients have been measured and results thereof have been reported (Supra, Revokatov). The results show that the measurement of longitudinal axis relaxation time of the serum may be used as a fast and massive cancer disease diagnosis method.
In a study by Koivula et al., a blood component that affects longitudinal axis NMR relaxation time of protons of water in a malignant blood disease was investigated and 55 blood samples were studied (the samples come from 20 healthy persons and 35 leukemia, myelofibrosis and multiple myeloma patients). The relaxation time measurement was conducted at a resonance frequency of 19.8 MHz and a temperature of 33±1° C. The relaxation time elevated over a normal level appeared in entire blood, packed cell, and blood plasma of the patients with blood disease. This relaxation rate depends on a ratio of dried solid to water. This corresponds to a three-state fast-exchange relaxation model (Supra, Koivula).
It could be concluded from the Denis study and related documents that the relaxation time is increased in tissues and in organism body fluids, particularly blood, affected by different diseases
Typically, interstitial fluid is closely contiguous to all of these body fluids and its composition thereof is almost that of blood plasma. The change of blood plasma relaxation time is expected to be reflected to the interstitial fluid to some extent. This change may be tracked at all positions of the organism.
An NMR imaging apparatus and a relaxometer have not been widely used in organ diagnosis because of costs and complexity. However, this situation is changing in recent years. A compact and inexpensive NMR apparatus has been invented and disclosed. For example, such an apparatus is disclosed in U.S. Pat. Nos. 4,875,486 and 6,404,197B1. These patents provide an apparatus for noninvasive spectral measurement for dextrose content of blood. These methods are not used in a medical field because chemical components of the blood affect one another on the NMR spectrum of the blood. However, the inventions may provide a small-sized NMR apparatus for users and doctors. Recently, a small-sized NMR relaxometer is disclosed in Russian Patent RU 33235 U1. This patent discloses the design and principle of a compact magnet relaxometer. This relaxometer is intended to measure longitudinal axis relaxation time of in vitro blood and of in vivo finger tissue. In studies by Protasov et al. and Esicov, these patents revealed that blood relaxation time linearly depends on dextrose concentration. They found that relaxation time measured by the NMR relaxometer after food ingestion is increased with time, and there is a correlation between the time and blood dextrose content. It can be seen from the data that blood relaxation time T1 changes from 0.6 s to 1 s when the dextrose concentration is changed from 4 to 12 mmol/L.
The same linear dependency appeared when the relaxation time of the finger tissue, other than the blood sample, was measured. In this case, however, the change in the relaxation time was much smaller, 0.33 s-0.48 s, and was within the same range of the dextrose concentration (Protasov E. A., Esikov O. S., Karpova E. S. Measurement of concentration of glucose in human blood by NMR method. Scientific conf. MEPhI-2003, v. 5, p. 38., Esicov O. S., Protasov E. A. Magneto-resonant method of measurement of spin-lattice relaxation time on the base of the size of absorption signal. Scientific conf. MEPhI-2003, v. 4, p. 46.). This could be explained by the fact that the dextrose concentration in a tissue cell is very small but an amount of blood and interstitial fluid proportional to all finger tissues are approximately 30%. This assumption is not yet verified and the dextrose selectivity of this sensor is under study. Such an increase in the relaxation time may be caused by an increase in blood metabolism after food ingestion. An experiment in which dextrose is added to a blood sample hardly exhibits the increase in the relaxation time. A final conclusion or explanation as to an accurate mechanism affecting the spin-lattice relaxation time of the blood and tissue during a day's period and in the case of disease is not yet obtained, but it is desirable that the relaxation time of peripheral tissues is independent of the relaxation time of only independent blood to increase effects of this factor.
A state of water within an organism tissue can be easily changed by chemical organic process. This phenomenon leads to relaxation time sensitive to an abnormal state of water in a cell and body fluids of a tissue. A number of abnormal states and a pathological processes may affect the state of the water molecule in the cell. This complicates attempts to use the relaxation time as an identification factor in medical diagnosis. However, complications need to be considered from alternative view points When most of the pathology states and abnormal processes of the tissue that change cell metabolism affect the relaxation time, the relaxation time may be used as a kind of universal factor characterizing a cell state.
The same situation is applied to the blood. Blood is a universal body fluid of all organisms and tissues. An organism exchanges a number of chemical components with blood. If disease or food ingestion increases the exchange process in an organism, this is reflected to the relaxation time behavior of the blood. Blood metabolism is low and relaxation time is short at during relatively quiet state, for example, night or between food ingestions. Food ingestion promotes a significant increase in the exchange process and increases metabolism. This leads to increases in the blood relaxation time. When an organ of an organism has a disease, a metabolism process is higher than the healthy state because the organ with disease does not work at an optimal state. This organ has an increased metabolism process. In this case, increase in the blood relaxation time may be sensed but it is less than the increase associated with food ingestion. A difference between these increases is that for food ingestion, the relaxation time is returned to a normal minimum relaxation time level after 3 or 4 hours, while for disease, this elevated relaxation time persists.
A blood metabolism rate is affected by a physical load, an oxygen load, food ingestion, a pH state, a disease and other elements. Relaxation time behavior is also independent to some extent. There is also universal regularity. The recovery rate of the blood relaxation time indicates an organism's capability against a physical load of a disease and shows efficiency of a nutrition process. This element can be used to study a day's period of blood metabolism rate and the stability of an organism state under several situations. This information is very useful for science and organ prediction.
A nutrition state of a metabolism process in a body may be classified into two states of an absorption state and a post-absorption state. The absorption state is a state during ingestion and post-ingestion. During this state, food is digested and absorbed. In 24 hours of a day's period, the absorption state is kept during a first 12 hours and a post-absorption state is kept during a second 12 hours. In three mealtimes of a day period, the absorption occurs early morning, each mealtime, and four hours after each mealtime. During the mealtime or after the mealtime, several types of metabolites such as salt, acid, dextrose, amino acid, enzyme, and hormone flow into the blood. All of these components should be transferred to tissue cells. The main transfer action in the blood plasma is served by albumin protein. The capability of this protein to combine and transfer these metabolites is highly effective. It is well known that the protein capability of combining different components significantly depends on solution factors such as pH and ionic force. These factors are all changed during the absorption state. This increases the capability of the protein molecules to combine metabolites. Physically, this means that a change occurs in a surface charge distribution on a protein molecule. Protein molecule conformation and charge dispersion on the protein molecule surface significantly affects the structure and thickness of a hydration shell of combined water molecules. This results in the dependency of spin diffusion, proton exchange, and magnetization transfer between a water molecule and a protein molecule. Basically, enhanced combining capability of a protein molecule to nutrient means reduction of chemical attraction to water molecule. Hydrogen combination intensity and the thickness of a combined water layer are reduced. All of theses factors lead to the increase in longitudinal axis relaxation time of water molecule within blood. The same process may be found in disease. An organ with disease requires an increase in metabolism rate. This is because cell operation at a pathology state is not maximized and quick exchange and energy consumption is needed.
This problem may be addressed from the most general theory standpoint. All processes within living organisms proceed in a water-based medium. Water is a liquid having high polarity and has a unique inherent nature. All giant biologic molecules “operate” in this medium, and interaction of the giant biologic molecules with water molecules determines their nature and operation. Factors such as pH and ionic force most importantly affect processes in the biologic tissue and body fluids. Combination of a water molecule with protein, proton exchange and magnetization transfer rate, and cross relaxation rate depend on these factors, as well. Hydrogen nucleus assembly of blood may be regarded as an open linear system. The open nonlinear system exchanges mass and energy with other systems. The rate of a physical chemistry process in the blood directly affects the structure and symmetry of water molecules around protein in this mixture solution, and affects entropy of this system. The rate of the metabolism process changes during a day. This means that there is a period having low metabolism activity and a period having high metabolism activity.
Food or drink ingestion means that metabolism activity for blood increases. Movement of nutrient through an organism may be regarded as additional dispersion of materials and energy. If more materials or chemical components move through the blood, a load on the transfer and exchange system increases. This process has a very detailed and minute adjustment mechanism. However, generally speaking, this additional load increases a chaotic state of water molecules and leads to less symmetry of a water shell around a biologic transfer molecule. The combination intensity or degree of immobilization of the water molecule and the structure of a water shell around a giant molecule are changed when the metabolism rate increases. This is reflected to the change in the relaxation rate.
In a biologic organism, a main mechanism of the NMR relaxation is dipole-dipole relaxation. From the NMR theory, the relaxation rate is represented as follows:
                                          1                          T              1                                =                                    J              ⁡                              (                ω                )                                      +                          J              ⁡                              (                                  2                  ⁢                  ω                                )                                                    ,                                  ⁢        and                            Equation        ⁢                                  ⁢        2                                                      1                          T              2                                =                                    J              ⁡                              (                0                )                                      +                          J              ⁡                              (                ω                )                                      +                          J              ⁡                              (                                  2                  ⁢                  ω                                )                                                    ,                            Equation        ⁢                                  ⁢        3            where, J(ω) is a spectrum density function of spin rotation. This is an index of power portion at a frequency ω. Water molecules at a liquid state have very short rotational, correlation on the order of 10−11s. Biologic molecules have greater correlation time. Particularly, large protein molecules have correlation times of 10−9 or 10−7 s. If the NMR relaxometer sensor uses a frequency of several tens of MHz, then giant biologic molecules have a much greater spectrum density fiction than that of water molecules at this frequency. This result indicates that the protons of these molecules relax much faster. The protons of these molecules relax at in a higher speed than that of water molecules within a solution containing protein and other biologic giant molecules because of their interaction with the water molecules. In this process, the protein greatly contributes to the relaxation and immobilizes the water molecules to some extent. In this regard, there is always some symmetry or regularity, particularly, around the giant biologic molecules and the protein in the mixture solution. From detailed observation of the transfer and action of the protein and metabolite, it is apparent that an increase in metabolism activity means that the protein is closely related to molecule movement and the exchange process. This necessarily reduces at least a protein-water combination degree in a special molecule position, and reduces the regularity and symmetry of water shell around the protein. Water molecule immobilization is also reduced. However, all these processes lead to reduced spin transfer and cross relaxation between water and protein molecules and increased transverse axis and longitudinal axis relaxation time. It will be apparent from consideration of these facts that relaxation time is increased each time a load is applied to a transfer system and a metabolism system. Food ingestion may be regarded as an additional load. The same applies to an abnormal or destructive process in the organism. Severe disease of an organ or organism may be an additional load on the transfer system and the metabolism activity. Accordingly, it can be found that a number of diseases increase the relaxation time of the blood. Myelofibrosis and multiple myeloma or blood diseases, such as leukemia, increase the relaxation time of the blood (Supra, Koivula). Such consideration is fundamental and not yet detailed. Nevertheless, it helps to basically describe blood relaxation time behavior in pathology. The only disease reducing the relaxation time is a red blood corpuscle disease called hemolytic anemia, in which a Hienz antibody attached to a cell film is formed within a cell, which is denaturalized and extracted hemoglobin (Hb) (M. Sogami, N. Uyesaka, S. Era, and K. Kato. NMR in Biomedicene, 16, 19-28, 2003.). It is a common phenomenon that oxyhemoglobin is automatically oxidized into paramagnetic met-hemoglobin (Met-Hb) and is accelerated in Hienz antibodies that form red blood cells (RBC). It is well known that a paramagnetic ion significantly reduces T1 and T2 of water. It is also well known that a free radical has a paramagnetic nature and a very small amount of free radical significantly reduces the relaxation time. The free radical adversely affects the organism, and increases concentration within the organism only in some special situations. Consequently, this situation may be sensed by the NMR relaxometer sensor. It may be uncommon that diseases having opposite tendency with respect to the relaxation time simultaneously occur in the same organism. It can be concluded that control of the relaxation time of the blood serves as a diagnosis factor useful in the medical field and is more valuable as a universal sensor that affords early prediction of an organism in a diseased state. In addition, this sensor may be used to scientifically study a response of a metabolism system to different types of loads applied on the organism.
It will be apparent from the above discussion that the metabolism process directly affects NMR relaxation mechanism of the water molecule and increases the relaxation time. Actually, this process can be directly observed. It is known that longitudinal axis relaxation of the blood after food ingestion is increased in all cases. The same effect is obtained in a severe organism condition. It is already recognized from experiments that almost all normal processes in an organic system and an inorganic system have an optimal factor characterizing the processes. One of the most universal principles in nature is a minimum-operation principle. It is logical that evolved biologic organisms try to develop a metabolism system so that a transfer and exchange process has a possible minimum value in a minimum activity state. This is a rest state of the organism. In the case of a physical load such as disease or food ingestion, the metabolism system is activated and all metabolism processes are accelerated. This naturally requires additional energy consumption. In this approach, the factor called the blood relaxation time may be used to study a response of the metabolism system of the organism to different types of loads, for example to study a response of an organism to a load in a sportsman training program. This approach may also be used by doctors to study features of a disease recovery process. This approach may also be used for all persons to perform medical diagnosis using universal equipment. This equipment could be advantageously applied to diagnosis means of a healthy room. U. S. Departments of Health and Human Services have recently approved a standard test that exhibits dextrose metabolism. This test is conducted by tracking valid time of detecting C13 isotope from exhalation. The valid time of this test may be somewhat associated with recovery of increased relaxation time of blood. This is because that the factor is also directly related to the blood and tissue metabolism.
Noninvasive measurement of only blood spin-lattice relaxation time is critical. This is because a relative change upon measurement of relaxation time of blood and peripheral tissue is much smaller and may be affected by a state of peripheral tissue (as well as a blood state) and also by surface paramagnetic contamination. Therefore, it is very important to separate only blood relaxation time, which is not affected by peripheral environment.